Myelodysplastic Syndromes with I(17)(q10) and Prognostic Implications of Mutations of TP53 and SETBP1

• Published in: Blood 2014-12, Vol.124 (21), p.1910-1910
• Main Authors: Adema, Vera, Maria Jose, Larrayoz, Maria Jose, Calasanz, Palomo, Laura, Patiño-Garcia, Ana, Aguirre, Xabier, Hernández-Rivas, Jesús María, Lumbreras, Eva, Buno, Ismael, Martínez-Laperche, Carolina, Mallo, Mar, Garcia, Olga, Gomez-Marzo, Paula, Alvarez, Sara, Blazquez, Beatriz, Cervera, Jose, Luño, Elisa, Valiente, Alberto, Vallespi, Teresa, Vicente, Ana, Arenillas, Leonor, Collado, Rosa, Perez-Oteyza, Jaime, Sole, Francesc
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.1910.1910

INTRODUCTION Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid stem cell disorders highly prevalent in elderly populations. MDS are characterized by inefficient hematopoiesis, peripheral blood (PB) cytopenias, and increased risk of transformation to acute myeloid leukemia (AML; 20–30%). Around 50% of MDS patients carry at least one karyotoypic aberration, the most common being 5q-, -7/7q-, +8, 20q-, and isochromosome 17(q10) [i(17q)]. Isochromosome 17(q10) according to cytogenetic risk stratification is of intermediate prognostic significance when is observed as a single abnormality. As i(17q) has be postulated to be associated to recurrent mutational patterns we investigated the TP53 and SETBP1 mutational status in 31 untreated MDS patients harboring i(17q). METHODS Genomic DNA was isolated from fixed cells from bone marrow samples using QIAamp DNA mini-kit Qiagen. TP53 exons 5–9 and SETBP1 exon 3 were amplified using PCR. Amplification products were all purified and sequenced in an automated sequencer. Additionally, we studied the methylation status of TP53 in 21 of the 31 patients. Sequence analyses were performed with PyroQ-CpG analysis software. RESULTS SETBP1 mutational spectrum was characterized by the presence of non-synonmous point mutations, mainly located in residues 868-871 in 13 out of the 31 analyzed patients (41.9 %). In seven of the 13 positive cases, the mutations corresponded to heterozygous D868N, in 5 cases associated with an isolated i(17q) and with 1 additional abnormality in the remaining samples. Three of the 13 SETBP1 mutations were heterozygous G870S associated to i(17q) as a single abnormality. Another three patients had single heterozygous mutations S869G, and I871T along with an i(17q) as a single abnormality or D868Y in the context of a complex karyotype. Regarding TP53 mutations six of the 31 had non-synonymous point mutations. Two patients had mutations in exon 7, three had mutations in exons 5, 6, and 8, and one patient had an intronic mutation at the splicing recognition site. A statistically significant correlation was found between TP53 mutation and a complex karyotype (P=0.001), and between SETBP1 mutation and isolated i(17q) (P=0.001). Univariate analysis for overall survival (OS) found a statistically significant difference between non-mutated and TP53-mutated patients (14.1 months vs. 2.9 months, respectively; P=0.001), and between SETBP1-mutated and TP53-mutated patients (14.5 months vs. 2.